Results and Exploratory Biomarker Analyses of a Phase II Study CHANGEABLE: Combination of PD‐1 Inhibitor and Niraparib in GErm‐Line‐mutAted Metastatic Breast Cancer

ABSTRACT This phase II trial evaluated the efficacy and safety of combining niraparib with the PD‐1 inhibitor HX008 in patients with metastatic breast cancer who had germline DNA damage response (DDR) mutations. The study included 37 patients, divided into a primary cohort of HER2‐negative individuals with germline BRCA1/2 or PALB2 mutations ( n = 29) and an exploratory cohort of patients who were either HER2‐negative with other DDR mutations, had brain metastases, or were HER2‐positive ( n = 8). The main cohort achieved an objective response rate (ORR) of 76% and a disease control rate (DCR) of 97%, with a median progression‐free survival (PFS) of 7.3 months. The exploratory cohort had an ORR of 25% and a DCR of 75%, while patients with brain metastases showed a 40% ORR. Among treatment‐related adverse events of Grade 3 or higher, the most frequently observed were anemia (35.1%), thrombocytopenia (10.8%), and neutropenia (8.1%). No treatment‐related deaths were reported. Somatic XPO1 mutations correlated with better response. Somatic TP53 mutations significantly correlated with shorter PFS, while ASXL1 mutations correlated with longer PFS. This chemotherapy‐free regimen demonstrates promising efficacy and a tolerable safety profile in patients with metastatic breast cancer and germline DDR mutations, providing a novel therapeutic option for this patient population, even those with brain metastases.